Genetic variation of muscle structure and function underlies susceptibility to many health problems, such as recovery from nerve damage (atrophy and rehabilitation), severity of muscular dystrophies and neuromuscular disorders, ability at sports, aging (sarcopenia), and others. Muscle is also increasingly recognized as an important endocrine organ in metabolic syndrome (obesity and inactivity), and genetic variation in muscle also likely underlies much of the susceptibility to progression to type II diabetes. This application is to continue a successful research program in identifying the genetic factors influencing muscle strength and size. In the previous award period, we recruited over 1,000 subjects into a unilateral resistance training (non-dominant arm), with extensive phenotyping at eight sports medicine facilities. Original endpoints included muscle strength (1RM and MVC) before and after training, and muscle size using cross-sectional area by MRI. We have extended beyond the original aims to include semi-automated volumetric studies of all subjects, with highly reliable (R2 = 0.91-0.96) assessments of muscle, subcutaneous fat and cortical bone volume. Our genotyping of this population has begun to define the genetic underpinnings of genetic variation of 10 core phenotypes (muscle, bone, fat volume, muscle strength, and response of each to training). Recently, we have defined a 4 allele haplotype upstream of the AKT1 gene that is the strongest QTL for strength, bone size, and fat volume to date;it explains 9.0% of all population strength variation, 7.4% of bone volume variation, and 1.3% of subcutaneous fat variation. The specific aims of this competitive renewal are to continue analysis of this pre-existing cohort of subjects, both with regards to phenotyping (completion of volumetric studies, extension to individual muscle groups and focal size changes, development of a public access resource to the data) (Aim 1), and genotyping (new loci, validation of existing associations through testing of GUSTO and Health ABC cohorts, and. extension of haplotypes) (Aim 2). Aim 3 is focused on systematically defining the effects of the robust AKT1 associations with functional consequences of the component SNPs on AKT1 gene promoter function, and a potential Zinc finger transcript unit upstream of AKT1. The proposed research is likely to have broad implications for our understanding of normal human genetic variation in both health and disease. In addition, the understanding of genetic variation also will impact our knowledge of basic biochemical pathways dictating muscle structure and function.